Epidermal growth factor receptor (EGFR), also known as ErbB1 or HER-1, is a cell surface receptor that plays a major role in a variety of cellular responses. It is a member of four closely related receptor tyrosine kinases: ErbB1, ErbB2 (HER-2), ErbB3 (HER-3), ErbB4 (HER-4). Ligand binding to the extracellular domain of these receptors leads to homo- or heterodimerization, followed by receptor tyrosine phosphorylation and phosphorylation/activation of many signaling proteins involved in an array of cellular events. Key signaling pathways downstream of ErbB receptors include the PI3K/AKT/mTOR pathway, the Ras/Raf/ERK pathway, and the JAK/STAT pathway. ErbB activation results in an increase in DNA synthesis, cell growth, cell proliferation, cell differentiation, and cell migration, which perhaps is most clearly demonstrated in cancer cells. Indeed, the ErbB receptors have become major drug targets in cancer therapy. Overexpression or activating mutations in the kinase domain of the ErbB receptors are known to be associated with a variety of cancers.
ErbB1 overexpression or activating mutations in its kinase domain occur in many cancers, including, but not limited to, brain cancer, breast cancer, colon cancer, lung cancer, and head and neck cancer. Several ErbB1-targeting drugs are on market, including penitumumab, cetuximab, gefitinib, erlotinib and afatinib. Penitumumab (IgG2 isotype) and cetuximab (IgG1 isotype) are monoclonal antibodies, whereas gefitinib, erlotinib and afatinib are low-molecular weight tyrosine kinase inhibitors. However, many patients are either intrinsically insensitive to these agents or develop acquired resistance. Therefore, there is an ongoing and unmet need to develop novel therapeutic approaches to targeting ErbB1 in cancer. The present disclosure meets this need.